The present invention is directed to a pharmaceutical composition useful in the treatment of pain. More particularly, this invention is directed to a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug.
Throughout this disclosure, various publications are cited and are herein incorporated by reference to describe more fully the state of the art to which this invention pertains.
U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1R,2R or 1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim. Forsch., (Drug Res.), 1978, 28(I), 114. Tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like (Driessen, et al., Arch. Pharmacol., 1990, 341, R104). The Abstracts of the VIth World Congress on Pain, Apr. 1-6 (1990), disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim. Forsch., (Drug Res.), 1978, 28(I), 183), constipation (I. Arend et al., Arzneim. Forsch., (Drug Res.), 1978, 28(I), 199), tolerance (L. Flohe et al., Arzneim. Forsch., (Drug Res.), 1978, 28(I), 213) and abuse liability (T. Yanagita, Arzneim. Forsch., (Drug Res.), 1978, 28(I), 158). When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating. Despite these side effects, tramadol""s xe2x80x98atypicalxe2x80x99 combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently marketed as an analgesic.
Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and, as a result, cannot always be given repeatedly or at high doses. The side effect problems are well documented in the literature. See, for example, T. Reisine and G. Pasternak in xe2x80x9cGoodman and Gilman""s, The Pharmacological Basis of Therapeuticsxe2x80x9d, 9th edition; Hardman et al.; McGraw-Hill, New York, 1996; Chapter 23; pages 521-555 wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
To reduce the side effect problems of opioids, opioids have been combined with other drugs, including non-opioid analgesic agents, which lower the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of requiring less of each ingredient while producing a synergistic analgesic effect. Compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive (A. Takemori, Annals New York Acad. Sci., 1976, 281, 262). A combination of morphine and methadone, another opioid analgesic, exhibits an additive effect (R. Taber, et al., J. Pharm. Expt. Thera., 1969,169(1), 29). U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. See also, U.S. Pat. Nos. 4,587,252 and 4,569,937 which disclose other ibuprofen opioid combinations. Superadditive analgesia with a 1:125 mixture of butorphanol:acetaminophen (an opioid analgesic combined with a non-opioid analgesic) has been reported, whereas a 1:10 mixture did not show any statistically significant superadditive analgesia (A. Pircio, et al., Arch. Int. Pharmacodyn., 1978, 235,116).
As an analgesic, tramadol has been combined with both opioid and non-opioid analgesic drugs. Such compositions have exhibited synergistic effects in treating pain while using less of each ingredient to produce an equivalent degree of analgesia. Specifically, U.S. Pat. No. 5,516,803 discloses the composition of tramadol and a NSAID, particularly ibuprofen. U.S. Pat. No. 5,468,744 discloses tramadol plus any of oxycodone, codeine or hydrocodone and U.S. Pat. No. 5,336,691 discloses tramadol in combination with acetaminophen.
As a class, anticonvulsant drugs are not known to be useful in the treatment of pain. However, certain anticonvulsant drugs have been found useful in the treatment of neuropathic pain. U.S. Pat. No. 4,513,006 discloses a class of anticonvulsant drugs including the 2,3,4,5-bis-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamates known as topiramate. U.S. Pat. No. 5,760,007, which is herein incorporated by reference, further discloses topiramate as useful for the treatment of neuropathic pain.
In addition, anticonvulsant drugs have been combined with non-toxic blockers for the N-methyl-d-aspartate (NMDA) receptor. Such compositions have been described as useful in the treatment of neuropathic pain. For example, WO 98/07447 broadly discloses the combination of a neuropathic pain alleviating amount of an anticonvulsant drug, including gabapentin, lamotrigine, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan or L-5-hydroxytrytophan and an anticonvulsant potentiating amount of a non-toxic blocker for the NMDA receptor. This reference, however, does not teach the synergistic composition of the present invention.
Anticonvulsant drugs combined with NSAIDS or narcotic analgesics have also been described as useful in the treatment of pain. WO 99/12537 discloses a composition of the anticonvulsant compounds gabapentin or pregabalin in combination with the NSAID naproxen or with narcotic analgesics. Combinations of anticonvulsants and other drugs with opioid analgesics have been suggested (Donnadieu, S., et al., Pain Relief, Presse Medicale, 1998, 27/39, 2062-2069). These references, however, also do not teach the synergistic composition of the present invention.
Heretofore, no reference has disclosed a pharmaceutical composition comprising a combination of the centrally acting analgesic tramadol and an anticonvulsant drug demonstrating that such a composition has a synergistic effect while using less of each ingredient for treating conditions of pain and neurological or psychiatric disorders in mammals.
Therefore, it is an object of the present invention to produce a combination product with a tramadol material having improved properties. It is also an object of the present invention to produce a combination product with a tramadol material and an anticonvulsant drug wherein the combination has a synergistic effect while using less of each ingredient. It is another object of the present invention to produce a combination product with tramadol hydrochloride and an anticonvulsant drug selected from, but not limited to, topiramate, gabapentin, lamotrigine or RWJ-333369; wherein the combination has a synergistic effect while using less of each ingredient. A further object of the present invention is to provide a method for treating conditions of pain and neurological or psychiatric disorders in mammals.
Briefly, according to the present invention, there is provided a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective 50% effective dose (ED50) values, which ratio is from about 1:1 to about 300:1 or from about 1:1 to about 1:300.
An embodiment of the pharmaceutical composition of the present invention comprises a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 100:1 or from about 1:1 to about 1:100.
Another embodiment of the pharmaceutical composition of the present invention comprises a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 30:1 or from about 1:1 to about 1:30.
The pharmaceutical composition of the present invention is exemplified by a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1.
The pharmaceutical composition of the present invention is also exemplified by a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 2:1 to about 20:1.
The pharmaceutical composition of the present invention is further exemplified by a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:2 to about 1:8.
The pharmaceutical composition of the present invention is still further exemplified by a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20.
The present invention also provides a method for treating a condition of pain or a neurological or psychiatric disorder in a mammal in need thereof comprising administering to the mammal a therapeutically effective dose of a pharmaceutical composition for treating the condition of pain or the neurological or psychiatric disorder comprising a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 300:1 or from about 1:1 to about 1:300.
An embodiment of the method of the present invention comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 100:1 or from about 1:1 to about 1:100.
Another embodiment of the method of the present invention comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 30:1 or from about 1:1 to about 1:30.
The method of the present invention is exemplified by administering a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1.
The method of the present invention is also exemplified by administering a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 2:1 to about 20:1.
The method of the present invention is further exemplified by administering a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:2 to about 1:8.
The method of the present invention is still further exemplified by administering a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20.